EP0117779A1 - Pyridazine derivatives active on the central nervous system, their process of preparation and medicines containing them - Google Patents

Abstract

The invention relates to the pyridazine derivatives of formula: <IMAGE> in which R1 is H, a substituted or unsubstituted phenyl group, a naphthyl group, a cyclohexyl group, a 2-thienyl group, a 3-thienyl group or a group indolyl-3; R2 is H, an alkyl or phenyl group, R3 is H, an alkyl, phenyl or cyano group, Alk is (CH2) n or -CH2-C ^ C-. A process for obtaining said products and their application as medicaments.

Description

The present invention relates, as new products, to pyridazine derivatives substituted in position 3 by a carboxyalkylamino, alkoxycarbonylalkylamino, carboxamidoalkylamino, or cyanoalkylamino chain.

It also relates to a process for the preparation of these compounds and to the medicaments which contain, as active principle, at least one of said derivatives.

dans laquelle

• R désigne l'hydrogène, un groupe alkyle inférieur, un groupe phényle, un groupe phényle monosubstitué par un halogène ou un groupe nitro ou un groupe alkyle inférieur ou un groupe alcoxy inférieur ou un groupe hydroxy ou un groupe trifluorométhyle, un groupe phényle disubstitué par un halogène, un groupe naphtyle, un groupe cyclohexyle, un groupe thiényle-2, un groupe thiényle-3 ou un groupe indolyle-3;
• R₂ représente l'hydrogène, un groupe alkyle inférieur ou un groupe phényle;
• R₃ représente l'hydrogène, un groupe alkyle inférieur, un groupe phényle ou un groupe cyano;
• Alk représente un groupe (CH₂)_n où n est un entier égal à 2, 3, 4 ou encore un groupe 1,2-propynyle -CH₂-C≡C-
• R₄ représente :
  • - COOH
  • - COO-alkyle
  • - CONH
  • - C≡N

The compounds according to the invention correspond to the general formula:

in which

• R denotes hydrogen, a lower alkyl group, a phenyl group, a phenyl group monosubstituted by a halogen or a nitro group or a lower alkyl group or a lower alkoxy group or a hydroxy group or a trifluoromethyl group, a phenyl group disubstituted by halogen, naphthyl group, cyclohexyl group, 2-thienyl group, 3-thienyl group or 3-indolyl group;
• R ₂ represents hydrogen, a lower alkyl group or a phenyl group;
• R ₃ represents hydrogen, a lower alkyl group, a phenyl group or a cyano group;
• Alk represents a group (CH ₂ ) _n where n is an integer equal to 2, 3, 4 or also a 1,2-propynyl group -CH ₂ -C≡C-
• R ₄ represents:
  • - COOH
  • - COO-alkyl
  • - CONH
  • - C≡N

In the present application, lower alkyl denotes an alkyl group having from 1 to 4 carbon atoms and by lower alkoxy group an O-lower alkyl group.

The compounds (I) are capable of giving, with mineral or organic acids, addition salts. The present invention also relates to the addition salts which the compounds (I) provide with the pharmaceutically acceptable acids.

3 (R₄ = COO-alkyle inférieur I (R₄ = COO-alkyle ou CN) ou CN)The compounds according to the invention can be obtained from 3-chloro pyridazines suitably substituted 1 according to the following reaction scheme:

3 (R ₄ = COO-lower alkyl I (R ₄ = COO-alkyl or CN) or CN)

From the chloridated pyridazines in position 3, the corresponding 3-amino-pyridazines are prepared 3. In practice, the direct passage from the chlorinated derivatives to the amino derivatives proving to be impractical, the process is carried out via the hydrazine derivatives 2 obtained with good yields by heating at reflux of the chlorinated derivatives 1 with an excess of hydrazine hydrate. Compounds 2 by hydrogenation in the presence of a catalyst, such as Raney nickel, lead to compounds 3.

By action on 3 of a ω-halogenated ester X-Alk-COO-R ₄ where X represents a halogen, preferably bromine, and R ₄ represents a COO-lower alkyl group or the cyano group, the compounds (I) are obtained in which R ₄ represents a COO-lower alkyl group or a cyano group. The reaction is carried out by heating the reagents in a solvent, such as dimethylformamide, at a temperature between 50 and 100 ° C.

The compounds (I) where R ₄ represents a -COOH group are obtained from the compounds where R ₄ represents a -COO-lower alkyl group by saponification in an acid medium, preferably by heating with a hydracid, such as hydrochloric acid or hydrobromic acid, within acetic acid at a temperature between 20 and 100 ° C. The acid is isolated directly in the form of the salt corresponding to the hydracid used, by evaporation to dryness.

Finally, the compounds (I) where R ₄ represents a carboxamido group can be prepared, either from the corresponding esters (I) by the action of ammonia in solution in an aliphatic alcohol, such as methanol, or from nitriles (I).

In the particular case where Alk represents an acetylene group, the acids (I) are obtained by carbonation of the py _ridazine substituted in position ₃ by a group - _NH-Alk where _Alk is an acetylene group.

The 3-chloro pyridazines used as starting materials are known compounds or can be prepared according to known methods and in particular by the action of excess phosphorus oxychloride on the corresponding 2H pyridazones-3.

The following nonlimiting examples are given by way of illustration of the present invention.

Example 1 (Ethoxycarbonyl-3 propylamino) -3 methyl-4 (naphthyl-1) -6 pyridazine, hydrochloride.

a) - Hydrazino-3 methyl-4 (naphthyl-1) -6 pyridazine.

The mixture of 6.0 g of 3-chloro-methyl-4 (naphthyl-I) -6 pyridazine and 4.8 g of hydrazine hydrate is heated to reflux for 4 hours. By cooling, it forms a. precipitate which is wrung and washed with water. Recrystallized from methanol. Mp: 206 ° C.

b) - Amino-3 methyl-4 (naphthyl-1) -6 pyridazine.

To the solution of 5.0 g of the hydrazino derivative obtained above in methanol, 2 g of Raney nickel are added and the mixture is hydrogenated at room temperature under an atmosphere for 72 hours. The catalyst is filtered and the solvent is evaporated to dryness under vacuum. The residue is recrystallized from methanol. MP: 110 ° C.

c) - (3-Ethoxycarbonyl propylamino) -3 methyl-4 (naphthyl-1) -6 pyridazine, hydrochloride.

1.18 g of the amino derivative of paragraph b) are dissolved in the minimum amount of dimethylformamide and then 1.46 g of ethyl ω-bromo-butyrate is added. The mixture is heated at 80 ° C for 3 hours. After cooling, it is diluted with water and made alkaline with 1N sodium hydroxide. Extraction is carried out with ethyl acetate and the organic phase is dried over magnesium sulphate. It is evaporated to dryness under vacuum. The oily residue is taken up in a little methanol and bubbled hydrochloric gas in the solution until acid pH. Anhydrous ether is added and the precipitate is filtered off. It is recrystallized from isopropanol. MP: 168 ° C.

Examples 2 to 26

By operating as indicated above, but by varying the starting 3-chloro-pyridazines and / or the halogenated esters which are opposite to them, the compounds (I) below are obtained, gathered in table I.

Example 24 (Carboxy-3 propylamino) -3 methyl-4 (naphthyl-1)) - 6 pyridazine, hydrochloride.

1.8 g of the ester obtained in Example 1 are dissolved in a mixture of 81 ml of acetic acid and 9 ml of concentrated hydrochloric acid. The mixture is heated at 100 ° C for 9 hours and then evaporated to dryness in vacuo. The solid residue is recrystallized from isopropanol and provides the expected product. F: 260 ° C

Examples 25 to 46:

By operating as in Example 27 from the various esters of Example 1, the acids (I) appearing in Table II below are obtained.

Example 47 (Carboxy-3 propylamino) -3 methyl-4 (4-hydroxyphenyl) -6 pyridazine, hydrobromide.

A solution of 2 g of the acid from Example 30 in 20 ml of 48% hydrobromic acid is heated at reflux for 15 hours. After cooling, the solid which has formed is filtered off, which is washed with isopropanol and then with ether.

The solid is dried at 70 ° C under vacuum to obtain 2 g of the expected product. M) 260 ° C.

Example 48 (Carboxy-3 propyne-2 ylamino) -3 methyl-4 phenyl-6 pyridazine, hydrochloride.

4-methyl-6-phenyl (2-propyl-ylamino) -3 pyridazine is prepared by heating at 60 ° C. for 2 hours with 7 g of 3-amino-4-methyl-6-phenyl pyridazine and 9 ml of propargyl bromide. After evaporation of the excess propargyl bromide, the residue is taken up in 300 ml of anhydrous benzene and 1.77 g of sodium are added. The mixture is brought to reflux for 15 hours, then the solution is poured onto excess dry ice and left in contact for several hours.

The solvent is evaporated off, the residue is taken up in isopropanol and a stream of hydrochloric gas is passed through. The solid is drained and recrystallized twice from isopropanol. Mp: 101 ° C.

Example 49 (Carboxamido-3 propylamino) -3 (4-chloro-phenyl) -6 pyridazine.

1.3 g of the ester of Example 8 are dissolved in the base form in 100 ml of methanol, then the solution is cooled in ice and 13 g of ammonia are dissolved in the solution. The mixture is left stirring for 6 days at room temperature and then evaporated to dryness under vacuum. The residue is recrystallized from acetonitrile. The expected product is thus obtained (0.7 g). Mp: 170 then 180 ° C.

Example 50 (3-Cyano propylamino) -3 4,6-diphenyl pyridazine, hydrobromide.

2.47 g of 3-amino-4,6-diphenyl pyridazine are dissolved in 5 ml of dimethylformamide and 1.63 g of 4-bromo-butyronitrile are added. It is heated to 60 ° C for 2 hours and allowed to cool. The crystals formed are drained and recrystallized from isopropanol. Mp 202-204 ° C.

Examples 51 and 52

• - la (cyano-3 propylamino)-3 méthyl-4 phényl-6 pyridazine, bromhydrate. F > 265° C
• - la (cyano-3 propylamino)-3 phényl-6 pyridazine, bromhydrate. F : 262-264°C.

By operating in the same way, but by varying the starting amino-3 pyridazine, we obtain in the same way:

• - (3-cyano propylamino) -3 4-methyl-6-phenyl pyridazine, hydrobromide. F> 265 ° C
• - (3-cyano-propylamino) -3-phenyl-6 pyridazine, hydrobromide. Mp: 262-264 ° C.

Example 53 (Carboxamido-3 propylamino) -3 methyl-4 phenyl-6 pyridazine, hydrochloride.

On dissout 3,33 g de bromhydrate du nitrile de l'exemple 51 dans 100 ml d'acide formique sec puis,en agitant, on fait barboter pendant 4 heures un courant d'acide chlorhydrique gazeux sec avec un débit d'environ 5 litres/heure. On évapore à siccité sous vide en chauffant le moins possible. Le résidu est repris dans l'éthanol et on ajoute de l'éther anhydre. On essore les cristaux et on recristallise dans l'isopropanol. F : 130-132°C.

3.33 g of the nitrile hydrobromide of Example 51 are dissolved in 100 ml of dry formic acid and then, with stirring, a stream of dry gaseous hydrochloric acid is bubbled for 4 hours with a flow rate of approximately 5 liters /hour. It is evaporated to dryness under vacuum while heating as little as possible. The residue is taken up in ethanol and anhydrous ether is added. The crystals are drained and recrystallized from isopropanol. Mp: 130-132 ° C.

The products according to the invention have been studied with regard to their activity on the central nervous system. Activity on the displacement of y-aminobutyric acid from its postsynaptic receptor.

Method:

The neurochemical activity of the derivatives of the present invention on the GABA-ergic system was evaluated by measuring the displacement of γ-aminobutyric acid (GABA) from its postsynaptic receptor.

The study was carried out according to the method of ENNA and SNYDER (Brain Res. 100, 81-97, 1975).

The displacement experiment was carried out in vitro in the presence of a suspension of synaptic membranes and of tritiated GABA at the final concentration of 3.6 nM.

Results:

Comments:

The products of the invention have the ability to displace GABA from its synaptic receptor.

This in vitro study was supplemented by an in vivo study.

The following tests were used.

1- Activity on the motility of the mouse. Method:

The tranquilizer-sedative activity of the derivatives of the present invention was evaluated by measuring the spontaneous motility of mice using the actimetry test (JR BOISSIER and P. SIMON, Arch Int Pharmacocyn, 1965, 158, 212-221) .

The equipment consisted of Apelab type actimetric cages (L = 26 cm; 1 = 21.5 cm; H = 10 cm) crossed by two light rays which impress a photoelectric cell.

The animals were placed individually in the cages 45 minutes after the administration of the product orally: each crossing of a light beam was counted by an individual counter. The scores corresponding to the movements of the animals were recorded for 10 minutes. The batches consisted of 12 mice per dose.

2 - Effect on the antagonism of ptosis induced by reserpine. Method:

The antidepressant activity of the compounds was evaluated in the test of the antagonism of ptosis to reserpine in mice.

This study was carried out on batches of 10 female mice of 20 + 1 g. The products were administered by the ip route at the same time as reserpine (2 mg / kg, iv). The mice were observed individually 1 hour after the administrations. Animals which did not show ptosis during the 15 seconds of the observation were considered to be antagonized. All control animals having received only the vehicle and reserpine presented ptosis. The median effective dose of antagonism (ED ₅₀ ) was evaluated by the probit method.

3 - Effect on rotational behavior in mice after unilateral lesion of the nigro-striated pathway with 6- (OH) dopamine. Method

The influence of the derivatives of the present invention on the central dopaminergic system was evaluated on the rotatory behavior in mice after unilateral lesion of the nigro-striated pathway by 6- (OH) dopamine (P. PROTAIS and J. COSTENTIN, J. Pharmacopol, 7 (2), 251-255, 1976).

Female Charles River CDl mice, weighing 20 to 24 g, were previously subjected to a unilateral lesion of the striatum by stereotaxic injection of 6- (OH) dopamine at a rate of 8 μg per animal. One week after this operation, the product to be studied was administered intraperitoneally to groups of 7 mice. The number of rotations was evaluated for 2 minutes, 1 hour after the administration of the product. Rotations ipsilateral to the lesion were counted positively, those contralateral were counted negatively. The algebraic sum of rotations for a group of treated animals was compared with that of the group of control animals having received only the vehicle (physiological saline).

The results obtained with one of the representative products of the invention, namely the product of Example No. 40, appear in Table III below.

The tests thus carried out show that the products according to the invention act on the neuron by occupying the receptor site for γ-aminobutyric acid. They have pharmacological properties in animals which can lead them to be used in human therapy for the treatment of neurological or neuromuscular mental disorders.

In particular, the products according to the invention can be used for mood or behavioral disorders such as depressive states, asthenia, Parkinson's disease, eating disorders or insomnia.

These products can be administered orally or by injection. The pharmaceutical compositions can be solid or liquid and can be presented, for example, in the form of tablets, capsules, granules, suppositories or injectable preparations.

The dosage can vary within wide limits, in particular according to the type and severity of the condition to be treated and according to the method of administration. Most often in adults orally, it is between 0.050 and 0.500 g per day, possibly divided into several doses.

By way of example, the following galenical preparation can be indicated:

Claims (9)

1. Amino pyridazine derivatives substituted in position 3, characterized in that they correspond to the general formula:

in which : . R ₁ denotes hydrogen, a lower alkyl group; a phenyl group, a phenyl group monosubstituted by a halogen or a nitro group or a lower alkyl group or a lower alkoxy group or a hydroxy group or a trifluoromethyl group, a phenyl group disubstituted by a halogen, a naphthyl group, a cyclohexyl group, a thienyl-2 group, a thienyl-3 group or an indolyl-3 group; . R ₂ represents hydrogen, a lower alkyl group or a phenyl group; . R ₃ represents hydrogen, a lower alkyl group, a phenyl group or a cyano group; . A _lk represents a group (CH ₂ ) _n where n is an integer equal to 2, 3, 4 or alternatively a 1,2-propynyl-CH ₂ C≡C- group; . R ₄ represents: - COOH - COO-alkyl - CONH ₂ - C≡N
and the addition salts of said derivatives with acids. 2. Method for obtaining the pyridazine derivatives of formula (I) in which Alk is a group (CH ₂ ) _n , according to claim 1, characterized in that it consists: 1) reacting a chlorinated pyridazine in position 3 of formula 1:

with an excess of hydrazine hydrate NH2-NH2 to form the pyridazine of formula 2:

2) to transform the pyridazine of formula 2 into the corresponding 3-amino pyridazine of formula 3 by catalytic hydrogenation; 3) reacting said 3-amino pyridazine with a ω-halogenated compound of formula X-Alk-COO-R ₄ in which X is a halogen atom and R ₄ is a COO-alkyl group or the cyano group to provide the compound of formula (I) in which R ₄ is as defined above; and 4) optionally converting the compound of formula (I) thus obtained into a compound of formula (I) in which R ₄ is the group COOH or CONH ₂ . 5) and optionally converting the derivatives obtained into addition salts with acids. 3. Method according to claim 2, characterized in that step 4) consists of a saponification of the compound of formula (I) in which R ₄ is the COO-alkyl group to form the corresponding acid, namely the compound of formula (I) in which R4 is -COOH. 4. Method according to claim 3, characterized in that the saponification is carried out in an acid medium. 5. Method according to claim 4, characterized in that the saponification is carried out by heating with a hydracid, such as hydrochloric acid or hydrobromic acid within acetic acid at a temperature between 20 and 100 ° C. . 6. Method according to claim 2, characterized in that step 4 consists in the transformation of the compound of formula (I) in which R ₄ is the COD-alkyl group or the cyano group into the compound of formula (I) in which R ₄ is a carboxamido group. 7. Process for obtaining the pyridazine derivatives of formula (I) in which Alk is an acetylene group such as 1,2-propynyl, characterized in that it consists in subjecting to a carbonation the corresponding pyridazine substituted in position 3 by the group -NH-Alk in which Alk is an acetylene group. 8. Medicines active in particular on the central nervous system, characterized in that they contain a pyridazine derivative according to claim 1. 9. Medicines according to claim 8, characterized in that they are packaged for administration by oral or injectable route.